One of the most disturbing things about the ongoing coronavirus disease 2019 (COVID-19) pandemic is the unpredictability of the eventual outcome of the infection. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease is asymptomatic in most cases but can be fatal in some.
The ability to identify the small but significant minority of infections that will progress to life-threatening COVID-19 is crucial to controlling the mortality rate of this public health crisis, which has already taken over 2.5 million lives.
A new study, which has been released on the bioRxiv* preprint server, reports the potential of the cell surface marker, CD47, as a biomarker for hyperinflammation, a characteristic feature of severe COVID-19.
With limited therapeutic options and vaccination expected to take months, if not a year, before adequate coverage is achieved, the prospects of rapidly containing the pandemic are dim indeed. They are not improved by the emergence of vaccine-resistant variants.
Many antivirals may be effective, at least in part, in reducing the death rate from SARS-CoV-2 infection if they can be administered early in the course of the disease. The current study was aimed to provide a rationale for the exploration of this biomarker as a way to identify the need for early antiviral therapy.
CD47 in immune evasion
CD47 is a cell surface glycoprotein expressed on a wide variety of cells. It is a receptor for thrombospondin-1 and a counter-receptor for the signal regulatory protein-α (SIRPα). It binds to the latter to prevent macrophage and dendritic cell activation and to the former to prevent T cell activation.
When expressed at high levels, CD47 allows immune escape of malignant and virus-infected cells.
CD47 levels in SARS-CoV-2 infection
An earlier study showed that in cell cultures of multiple SARS-CoV-2-infected human cell lines, including colorectal carcinoma cells, primary human bronchial epithelial cells (HBEpiC) grown in an air-liquid interface (ALI), and Calu3 cells representing human lung epithelium, CD47 was expressed at higher levels.
Lung samples from deceased COVID-19 patients also showed high CD47 expression.
Aging-related increase in CD47
Further research of existing literature turned up the reported evidence that the known increase in COVID-19 risk and mortality with aging is linked to the similarly increased levels of CD47 with age.
CD47 signaling reduces the activation of soluble cellular second messenger molecules, mediated by nitric oxide (NO), which is responsible for vasodilation. This reduction causes hypertension in some individuals.
Aging-related CD47 and vasculopathy
The loss of this signaling pathway, or its inhibition, in a mouse model, can thus block the vascular disease of age or associated with a faulty diet. It was found to reduce ischemic injury as well.
Mice deficient in CD47 had low blood pressure, indicating that this molecule has vasopressor activity. These mice also used energy and food more efficiently and had a lower body weight.
The increase in CD47 in pulmonary hypertension is partly responsible for pulmonary arterial vasculopathy. This increase in CD47 with age also reduces blood flow in the limbs, and wound healing, in mice.
This signaling pathway, via thrombospondin-1, also triggers endothelial senescence with age, as well as other undesirable changes in vascular growth and function, besides energy management in the body.
This molecule was also expressed at high levels in many other clinical situations associated with hypertension. Anti-CD47 antibodies prevented and reversed fibrosis in many different organs in mice, indicating their potential for managing pulmonary fibrosis in COVID-19.
The vasopressor effects of this molecule are thus potentially important in triggering vascular pathologies in COVID-19. These include pulmonary hypertension, lung fibrosis, heart attacks, strokes and acute renal injury. It is also thought to have immunosuppressive activity.
CD47 in diabetes
In animal studies with hyperglycemia, the high glucose levels prevented the degradation of CD47, which in turn led to its increase in diabetic rats. This may prevent the immune recognition of virus-infected cells and allow the virus to replicate within the infected cells.
Again, with obesity, there may be an indirect link with CD47 levels and thus with diabetes. The known increase in the risk of diabetes and hypertension with obesity could contribute to the danger of severe COVID-19 in obese individuals.
What are the implications?
The study demonstrates the association between SARS-CoV-2 infection and higher levels of expression of the cell marker CD47. This has been shown to have immunosuppressive activity by binding to its receptor and coreceptor, as described above.
The expression of human CD47 has been thought to prime the body for organ transplantation from pigs into human recipients and to promote immune evasion by cancer cells. Its ability to reduce immune responses has led to its potential for use as a therapy against infections, including SARS-CoV-2 infection.
These findings indicate that CD47 may be an important drug target in enhancing antiviral immunity.
The role of aging in increased CD47 expression may partly, at least, explain why older people are so much more at risk of severe or fatal COVID-19. High CD47 levels are also associated with vasculopathy and hypertension. This may contribute to the higher risk of various vascular complications in severe SARS-CoV-2 infections, such as strokes, heart attacks and pulmonary hypertension.
The involvement of increased CD47 in the deleterious effects of high blood glucose levels and frank diabetes may also explain the high risk of adverse outcomes associated with severe COVID-19 in people with diabetes and obesity, since this promotes both hyperglycemia and hypertension.
The study therefore identifies CD47 as a candidate biomarker that may predispose towards severe COVID-19 at high levels. Further study is required to validate its role as a reliable predictor of progressive severe disease following SARS-CoV-2 infection, so as to identify those patients who will benefit from early antiviral therapy.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.